Alkyl esters of substituted thiocyanooctanoic acids



United States Patent F ALKYL ESTERS 0F SUBSTITUTED THIOCYANO- OCTANOICACIDS a Carl S. Hornberger, Jr., Wilmington, Del., assignor to E. I. duPont de Nemours and Company, Wilmington, Del., a corporation of DelawareNo Drawing. Original application May 28, 1954, Serial No. 433,281.Divided and this application April 26, 1955, Serial No. 504,115

7 Claims. (Cl. 260-454) This invention relates to processes. forpreparing alphalipoic acid and homologs thereof and to novelintermediates employed in their preparation. More particularly, theinvention is concerned with a process for preparing a cyclic disulfideof the formula Patented July 30, 1957 commercially practical because ofthe small amount to be found in nature and because of ditficulties inisolation. Several routes for its synthesis by chemical means have beendeveloped which make use of an oxidative ring closure using adimercaptooctanoic acid as an intermediate. This oxidative ring closureis accompanied by polymer formation. When an cxidant other than iodineis used, there is a danger of forming higher oxidized products. Adisadvantage to the use of iodine is its cost.

I have now found that a compound of Formula 1 can be prepared without anexternal oxidant and with a minimum of polymer formation by the alkalinetreatment of a dithiocyano derivative of a fatty acid ester having theformula 2. R0OG(CH2)4CHOH2CH2SCN where R is a lower alkyl groupcontaining from 1 to 6 carbon atoms.

This alkaline reaction which leads to ring closure is conducted in arelatively concentrated solution and without regard to a balancedstoichiometry with reference to the ring closing agent.

The dithiocyanate derivative of a fatty acid ester represented byFormula 2, which is reacted with alkali to form, after acidification,lipoic acid, can be prepared from hydroxy or halogen-substituted fattyacid esters, or esters containing both hydroxy and halogen groups, by asequence of reactions with salts of thiocyano acid or treatment with anorgano sulfonyl halide followed by treatment with a salt of thiocyanicacid. This sequence of reactions is graphically shown below.

RSOaCl b. elcid acceptor RSOzCl acid acceptor c. d. MSCN e. MSCN OS02R'SON SON I ROUTE B 7. R0 00 (CH2)4-CHCHz-CH:

R'SOaCl MSCN f. 1. acid acceptor SUN H 1 802B R'SOzCl acid acceptor g I.MSCN MSCN SON SOzR' SCN SON metal poisoning, and as a food supplement toimprove the diet of animals.

The isolation of lipoic acid from natural sources 1s not InRoutes A andB, R has the same significance as in Formula 2, R is alkyl, aryl oralkaryl, and M represents alkali metal or ammonium.

a a a a ROUTE C 11. ROOC(CHz)4CH-CH1CH2 7 R/SOzOl 7 acid acceptor k.

12. R0 0C (CHfir-CH-CHa-CFI:

OSOzR' OSOnR' MSCNll. 2. R00C(GHz)4-CHoH -oH,

SON SON R, R, and M have the same-significance as in Route A.

ROUTE D s. noooromn-orkofn-om hal hal MSCNl 1n.

2. R000 (CHQFCH CHrCEh SON SCN .R, M have the same significance as inRoutes A, B and C, and hal represents a halogen of the class consistingof chloro, bromo and iodine.

Illustrative. of the. compounds which maybe used as starting materialsin Routes A, B, C or D, there may be mentioned the following:

Methyl 8-chloro6-hydroxyoctanoate Methyl 8-bromo-6-hydroxyoctanoateEthyl 8-chloro-6-hydroxyoctanoate Propyl 8-chloro-6-hydroxyoctanoatet-Butyl 8-chloro-G-hydroxyoctanoate n-Butyl 8-chloro-6-hydroxyoctanoateSec-butyl 8-chloro-6-hydroxyoctanoate Iso-amyl8-chloro-6-hydroxyoctanoate n-Arnyl 8-chloro-6-hydroxyoctanoate Hexyl8-chloro-6-hydroxyoctanoate Methyl 6,8-dibromooctanoate Ethyl6,8-dichlorooctanoate Methyl 6,8-dihydroxyoctanoate Ethyl6,8-dihydroxyoctanoate Methyl 6-chloro-S-hydroxyoctanoate t-Butyl6-chloro-8-hydroxyoctanoate Ethyl 6-bromo-8-chlorooctanoate Ethyl8-bromo-6-chlorooctanoate Ethyl 6-chloro-8-iodooctanoate Ethyl6,8-diiodooctanoate Compounds of Formula 3, and of Formula 13 Wherehalogen is chlorine, are fully described and claimed in the copendingapplication of Donald S. Acker, Serial No. 433,800, filed June 1, 1954.In brief, these compounds can be prepared from the Friedel-Craftsaddition of an olefin to an acid chloride derived from a half acidester.

Broadly speaking, compounds of Formulae 3, 7, 11 and 13, that is, thestarting materials for Routes A, B, C and D, can be prepared inaccordance with the synthesis outlined hereafter, and X is a halogenhaving an atomic number above 9.

Referring to Routes A and B, it will be noted that in step b or i, thehydroxychloro compound is mixed with an organo sulfonyl chloride,preferably in a solvent. An acid acceptor, such as for instance, atertiary amine or a weak organic base, may be added to remove thebyproduct mineral acid. An excess amine may be used as a solvent or aninert diluent may be used.

The intermediate halosulfonic ester of Formulae 5 and 9 can be isolatedor treated in the same solvent with a salt of thiocyanic acid to producethe desired dithiocyano derivative of a fatty acid ester of Formula 2.

An alternative route comprising steps a, c, and e is to treat thehydroxychloro compound of Formula 3 with a salt of thiocyanic acid toproduce a hydroxy thiocyano compound of Formula 4. This hydroxythiocyano compound can then be treated in a solvent with an organosulfonyl halide in the presence of an acid acceptor. The solvent may beinert or a tertiary amine. Theresultant thiocyanosulfonic ester ofFormula 6- can then be treated with a salt of thiocyanic acid to givethe dithiocyano derivative of a fatty acid ester of Formula 2.

Another method of preparing a compound of Formula 2 is illustrated bysteps k and 1 starting with a dihydroxy compound of Formula 11. A doublequantity of the organo sulfonyl halide is employed with a weak base toyield a double sulfonic acid of Formula 12, followed by treatment with asalt of thiocyanic acid.

The conversion of the dihalo compound of Formula 13 to the dithiocyanocompound involves treatment with a salt of thiocyanic acid.

Among the preferred organo sulfonyl halides are methane sulfonylchloride and toluene sulfonyl chloride. Other sulfonyl halides may,however, be used but they are generally more expensive. Methane sulfonylchloride is particularly preferred because of its low molecular weight.

Any of a variety of compounds may be used as the acid acceptor includingtertiary amines or weakly basic inorganic salts such as, for instance,sodium carbonate, sodium bicarbonate or calcium carbonate. Pyridine andtriethylamine are preferred acid acceptors because they also function assolvents. If desired, the tertiary amine may be diluted with an organicsolvent such as benzene or ether to minimize cost.

The preferred salts of thiocyanic acid which are em- 7 ployed in theprocesses of this invention are potassium or sodium thiocyanate.Ammonium thiocyanate or other metal thiocyanates such as, for instance,calcium, may be used but the rate of reaction is slower when they areused in contrast to when alkali metal thiocyanates are employed.

Although the replacement of the organo sulfonyl or halo group with themetal thiocyanate can be conducted at a high temperature at which thesalt is molten, it is preferred to conduct the reaction at more moderatetemperatures in the presence of an inert solvent such as, for instance,benzene. In order to increase the solubility of the thiocyanate saltdimethyl formamide may be used to form a more soluble complex with thesalt.

The conversion of dithiocyanates of Formula 2 to alpha-lipoic acid or ahomolog thereof by alkaline treatment is effected in solution. Aconvenient reaction me- .Alchl CH2=CH5 dium is an alcohol such as, forinstance, ethanol. Anhydrous alcohol is not essential. In fact, in someinstances, better yields are obtained when some water is present. Inorder that the reaction may be completed in a reasonable time a strongalkali such as sodium or potassium hydroxide is preferably used. Forthis same reason, the temperature preferred is about the boiling pointof the solvent. The use of a strong base also brings about a cleavage ofthe ester group so that the free acid may be isolated afteracidification. An oxygen-free atmo'sphere is preferred. This reduces theoxidation of lipoic acid which may take place under alkaline conditions.As regards the isolation of the resulting lipoic acid, or homologthereof, convenient practices used in the isolation of a fatty acid maybe followed.

Considering in more detail the formation of the organosulfonyl ester, itshould be pointed out that a preferred method is to add the sulfonylhalide to a solution com prising a hydroxy compound of Formulae 3, 4, 7,8, or 11 and a.tertiary amine. The hydroxy compound may be added to amixture of sulfonyl halide and tertiary amine. The addition of thetertiary amine to a mixture of the hydroxyl compound and sulfonyl halideis less desirable. When a sulfonyl halide and the hydroxyl compound aremixed, a diflicultly controlled spontaneous reaction may occur. Thisleads to by-products.

Ordinarily, the hydroxyl compound and the sulfonyl halide are employedin about equimolar amounts. The tertiary amine is used in from 10 to 30%excess in the event an inert solvent is used. Otherwise, the amine isused in larger amounts sufiicient to dissolve all reactants. Thehydroxyl compounds, sulfonyl halide and tertiary amine should be as freefrom water as possible because the sulfonyl halide is destroyed inamounts corresponding to the amount of water present. For this reason,an atmosphere of dry nitrogen is often used to prevent reaction withatmospheric moisture.

The temperature range for satisfactory reaction of the sulfonyl halidewith the hydroxy substituted compound is in the range of from to 20 C.Some decrease in yield is noted at temperatures above 20 C. Above 40,the yield drops substantially. Below 5 C. the reaction proceeds slowly.

The sulfonyl halide-hydroxy compound reaction as judged by theprecipitation of the by-product amine salt proceeds to near completionwithin two hours. No decrease has been observed when the reaction timehas been increased to about 18 hours.

Inasmuch as the reaction between the sulfonyl halide and the hydroxysubstituted fatty acid ester proceeds with the formation of aprecipitated salt, stirring is preferable to prevent unchanged reactantsfrom being occluded to the precipitate. Stirring helps to maintain ahomogeneous state in the liquid phase.

As regards the isolation of the organosulfonyl ester of Formulae 5, 6,9, 10, 12 the reaction mixture is filtered after the reaction iscompleted to remove the precipitated salt. Alternatively, the by-productsalt can be removed by washing with cold water. Evaporation in vacuo ofthe solvent at a pressure less than 40 mm. mercury and a temperature ofless than 50 C. is practised to obtain the sulfonyl ester as a crudeoil. However, the sulfonyl ester can be used in solution without thenecessity of evaporation if the salt is removed. When an amine is usedas an acceptor, the by-product amine salt can be removed bydecomposition with sodium bicarbonate.

' The replacement of the organo halide by a thiocyanate salt in theprocesses of my invention involves mixing the substituted organic esterwith a thiocyanate salt, preferably in the presence of a solvent,bringing the reactants to reaction temperature. Without the presence ofa solvent the replacement of the halogen by the isocyanate grouprequires a temperature in the range of from 170 to 200 C. Thistemperature is necessary to melt the alkali thiocyanate. However, in.the presence of an ameliorating solvent such as dimethylformamide, atethperature of from to 160 C. is practical. At lower temperatures thereaction takes a longer time and at higher temperatures the product maybe discolored.

Generally speaking, about equimolar amounts of the substituted organicester and thiocyanate salt are used. A slight improvement in yield isoften realized in the presence of an excess of thiocyanate salt.

The replacement of the negative organohalide group by a thiocyanate maybe conducted in the fused state. It is preferred, however, to use aninert solvent in which the inorganic as well as the organic componentsare soluble. Dimethylformamide is a preferred solvent because of theease with which it dissolves the inorganic salt. However, other solventssuch as, for instance, alcohols, ketones and esters, may be used. Thepresence of traces of Water seems to have no effect upon the reaction.

The reactants, that is, the organohalide and metal thiocyanate, must bebrought in good contact with each other in order for the reaction to becomplete. Intimate mixing is essential.

Since isolation of the sulfonyl ester in a pure state is not essentialfor the purposes of my invention the ester may merely be washed withwater to free it from the byproduct salt. No further purification isrequired.

The replacement of the sulfonyl ester by thiocyanate salt is effected bymixing and heating the reactants until a reaction ensues. Ordinarily,the sulfonyl ester and the thiocyanate salt are used inabout equimolaramounts. A slight increase inyield is sometimes obtained when about a 5%excess of the thiocyanate salt is utilized.

Since sulfonyl esters are sensitive to water in the presence of heat,the reactants should be as anhydrous as possible. However, rigorouslyanhydrous conditions are not critical.

Although the replacement of the sulfonyl ester may be accomplished infused thiocyanate salt, it is preferred to bring about the reaction at alower temperature in the presence of a solvent, preferably an inertorganic solvent such as benzene. A preferred solvent is dimethylformamide which forms a more soluble complex.

When the replacement of the sulfonyl esters of Formulae 5, 6, 9, 10 and12 by thiocyanate salt is conducted in solvent any temperature betweenthe freezing point of the solution and the boiling point may be used. Inorder to reduce the reaction time'the preferred temperature is fromabout 80 to C. When the reactants are heated in a solvent at 80 to 120C., the time of the reaction is short. About one hour is sufl'icient toinsure completion of reaction.

When the reaction, that is, step d, e, h, j, l, or m, is conducted inbenzene and dimethyl formamide, a formation of a gel is frequentlyobserved. Vigorous stirring is therefore required to insure an intimatemixing of the reactants. Because a compound of Formula 2 may be used inan impure state, in the processes of the present invention, a water washis sufiicient to remove the by-product salt.

In carrying out ring closure step of the processes of my invention, thedithiocyan-ate organo-ester is mixed with an alkaline solution and themixture maintained at a temperature of from 0 to C. To decrease reactiontime the mixture is preferably kept at a temperature near that ofreflux, that is, 50 to 100 C. Temperatures about 100 C. are notpreferred since pressure is then required. The ring closure is effectedin about 4 hours or less.

The dithiocyauate can be added to the alkali solution or the alkali canbe added to a solution of the dithiocyanate. One mol of thedithiocyanate organo ester requires a minimum of three molar parts ofalkali. An excess up to as much as ten parts of alkali may be used tospeed the reaction to completion. The presence of 75 water is desirablebecause under completely anhydrous conditions the formation of a cyclicdisulfide is complicated by the formationof other. products. V H V v Itis preferred to use a solvent in which both the thiocyanate compound andalkali are soluble. Such Solvents include alcohol and alcohol-watermixtures. 'Water alone may be used and the dithiocyanate goes intosolution as the reaction proceeds. Preferably, the dithiocyano compoundin alcohol is added as a single batch to an alcohol-water solution ofalkali. The alcoholic solution is stirred mainly to assist in even heattransfer and to promote even boiling.

After completion of the ring closure, the alkaline solution is made acidwith a mineral acid such as, for instance, hydrochloric acid or sulfuricacid. At this point, by-product inorganic salt usually separates and canbe removed by filtration. The filtrate containing lipoic acid or homologis reduced in volume by evaporation in vacuo. The majority of thealcohol present is thus removed from the system. The resulting mixturecomprising product salts and water is extracted with a solvent todissolve and remove lipoic acid or an analog thereof. Any of a widevariety of solvents may be used including benzene, toluene, ether andthe like. The lipoic acid is recovered from the solvent by distillation.It is recrystallized from a solvent such as for instance petroleumether, hexane or cyclohexane. When water alone is used as a solvent,only acidification and extraction are used to obtain crude lipoic acid.

The intermediate hydroxy chloro compounds of Formulae 3 and 7 are knownto be herbicides while the intermediate hydroxy thiocyano anddithiocyano compounds of Formulae 2, 4 and 8 are insecticides and areactive against such pests as weevils, aphids, and mites. The compoundsof Formulae 2, 4 and 8 are also active as herbicides.

In order to better understand the invention, reference should be had tothe following illustrative examples:

Example I PREPARATION OF dl-ALPHA-LIPOIC ACID Two hundred andseventy-two'parts by weight of monomethyl adipate, 3500 parts of drytetrachloroethane and 236 parts of thionyl chloride are heated slowlyuntil reflux temperature is reached. This requires about 45 minutes. foran additional half-hour. Hydrogen chloride and sulfur dioxide areevolved during the reflux period. A still head is placed on the flask inplace of a condenser and 100 parts of distillate are collected. The acidchloride in the flask is then cooled to 15-20".

To'the cooled reaction mixture 453 parts of anhydrous aluminum chlorideare added over a period of twenty minutes. Thru a tube leading to belowthe surface of the solvent, there is passed a rapid stream of ethylenefor a period of two hours while the temperature of the reaction mixtureis maintained at 25 15 C.

At the end of this period, the reaction mixture is poured into a rapidlystirred mixture of 2,000 parts of finely crushed ice and 250 parts ofconcentrated hydrochloric acid. The mixture is stirred for aperiod often minutes. The lower-phase is separated from the water and washed withtwo portions of water and two portions of. sodium bicarbonate solution.The time required for the decomposition and washing is about one'hour.

The solution thus obtained and consisting essentially of methyl8-chloro-6-ketooctanoate, whose formula is CHaOOC(CH3) 4COCH2CH2C1 Themixture is heated at reflux temperature tion of 18 parts of sodiumborohydride in 500 parts of alcohol is added over a fifteen minuteperiod. The reaction mixture. is stirred at a temperature of 10 C. for aperiod of 45 minutes. It is then heated to a temperature of 50 C. for aperiod of one-half hour to decompose the excess sodium borohydride. Themixture is cooled to 20-25 C. and made acid with concentratedhydrochloric acid to a pH of 1.0-2.0. The acidified mixture is washedwith three portions of water, each portion consisting of parts, and-oneportion of dilute sodium bicarbonate solution. The product, methyl8-chloro-6- hydroxyoctanoate,.is isolated by distillation following theevaporation of the solvent in vacuo. The boiling point of methyl8-chloro-6-hydroxyoctanoate is 131-135 C. at 0.1-0.2 mm. mercury. Theindex of refraction using sodium D light is 1.4620-1.4660 at 25 C.

A mixture consisting of 104 parts of methyl 8-chloro- -hydroxyoctanoateprepared as described above, 48 parts of potassium thiocyanate and 200parts of dry dimethyl formamide (dried by distillation) is stirred andheated. 'When the temperature of the mixture reaches about 100 C., thesalt goes into solution. At the temperature of 150 C. a precipitatebegins to form.

The precipitated salt can be removed by filtration. The majority of thesolvent is removed in vacuo at 20 mm. Hg and up to 100 C. The crude oilis taken up in 200 parts of tetrachloroethane and washed with five 200ml. portions of water. The addition of ferric chloride to a filteredportion of the wash water produces only a slight red color. The solventis removed in vacuo. The index of refraction of methyl6-hydroxy-8-thiocyanooctanoate is n 1.4940- :0.0040.

The methane sulfonic ester of methyl 6-hydroxy-8- thiocyanooctanoate isprepared by placing 58 parts of methyl 6-hydroxy-8-thiocyanooctanoate,30 parts of dry pyridine .and 100 parts of dry benzene in a vesselcooled to 15 C., and adding to the vessel 29 parts of methane sulfonylchloride over a period of 15 minutes. The temperature of the reactionmixture is allowed to rise to 25 ,C. The mixture is stirred for a periodof two hours. During this period the solution becomes filled with finecrystals of pyridine hydrochloride, which are removed by filtration.This filtration is elfected with care being taken to exclude moisture.

To a mixture comprising 300 parts of dry dimethyl formamide and 48 partsof potassium thiocyanate and heated to a temperature of about 0., thereis added the methyl 6-hydroxy-8-thiocyanooctanoate methane sulfonic acidester, from the previous step, at such a rate that the temperature ofthe reaction mixture does not drop below 130 C. During this addition,benzene is distilled out of the mixture.

After the addition is completed, the heating is continued for anadditional ten minutes. The reaction mixture is then cooled to about 110C. and 500 parts of dry tetrachloroethane is added. After the mixture iscooled to 15-20 C. it is filtered with the aid of Celite." The filtrateis washed with from two to five portions of water, that is, until theferric chloride test for thiocyanate is negative. Occasionally it may benecessary to clarify the two phase suspension of the first wash bypassing through Celite wetted with tetrachloroethane. The solvent isremoved invacuo.

The resultingdark oil consisting essentially of methyl6,8-dithiocyanooctanoate is dissolved in 1500 parts of denaturedalcohol. To the resulting solution there is added a mixture of 55 partsof potassium hydroxide. The mixture is heated under reflux for a periodof from 1 to 2 hours. The mixture is then cooled to 20 C. and "made acidwith concentrated hydrochloric acid to pH 1.0-2.0. The salts whichprecipitate can be removed by filtration. The solvent is removed invacuo. The residue is. extracted with benzene. The water layer is againextracted with a small portion of benzene. The combined benzene extractsare dried over sodium sulfate and evaporated in vacuo. The crude lipoicacid weighing 30 parts is purified by distillation in high vacuum usinga simple short path still heated by an oil bath at a temperature of200-230 C. The crude material boils at 185-195 C. at 0.5 mm. mercuryUpon cooling and seeding the crude lipoic acid, crystallization occurs,M. P. 54-56 C. The distilled lipoic acid can be further purified bydissolving in a minimum of cyelohexane at 50 C. and pouring into volumes(based upon the volume of cyclohexane) of low boiling petroleum ether.The purified dl-lipoic acid crystallizes in the cold after seeding togive material melting at 58 to 59 C.

Analysis.-Calcd. for CsHnOzSz: C, 46.57; H, 6.84; S, 31.08. Found: C,47.61, 47.30; H, 7.07, 6.94; S, 29.92.

Example 2 Nine hundred parts byweight of monoethyl .adipate is dissolvedin 6382 parts by weight of tetrachloroethane. To this mixture there isadded 700 parts of thionyl chloride. The mixture is stirred and heatedslowly so that at the end of one hour reflux temperature is reached. Themixture is maintained at reflux for a period of one-half hour. 200 partsby weight of tetrachloroethane is removed by distillation.

This reaction mixture consisting essentially of carbethoxyvaleric acidchloride is cooled by means of an ice bath to a temperature of 7 C.

To the cooled acid chloride there is added quickly 1350 parts ofanhydrous aluminum chloride. An excess of ethylene is then passed intothe solution for a period of three hours at a rate of about /2 part perminute. The temperature of the reaction vessel is maintained in therange of 20 to 25 C. At the ends of this period, the reaction mixture ispoured into 6000 parts of ice and 850 parts of concentrated hydrochloricacid. The resulting mixture is stirred for a period of ten minutes andthen the aqueous layer is removed by means of a siphon. The solventlayer is washed with three 3000 part portions of cold water and twoportions of 5% sodium bicarbonate solution. The washed organic solutionconsists essentially of ethyl ester of 8-chloro-6-ketooctanoic acid.

The ethyl ester is cooled to a temperature of about 8 C. A slurry of 54parts of sodium borohydride in 1500 parts of ethanol is added to theester over a period of about one hour. During this addition thetemperature of the mixture is maintained in the range of 5-15 C. Afterthe mixture is stirred for a period of two hours at a temperature of1525 C., 100 parts of concentrated hydrochloric acid is added. Theresulting mixture is filtered to remove the solid by-product salts andthen washed with water and dilute sodium bicarbonate. After removal ofthe solvent in vacuo, the product, ethyl 8-chloro-6-hydroxyoctanoate isdistilled. It boils at 160- 175 C. at a pressure of 0.1 to 0.2 mm.mercury. Its index of refraction at 25 C. is 1.4590:0.0010.

A mixture consisting of 350 parts of potassium thiocyanate, 1500 partsof dimethyl formamide, and 678 parts of 8-chloro-6-hydroxyoctanoate acidethyl ester obtained as above described is stirred and heated to atemperature of 120130 C. for a period of one hour. During this treatmentthe formation of a precipitate is noted. The reaction mixture is cooledand poured in the water. An oily organic product is collected with theaid of 500 parts of benzene. The organic layer is washed with successiveportions of water until a portion of the wash water gives only a slightpositive test for thiocyanate ion by the ferric chloride reagent. Thebenzene solution is then dried over anhydrous magnesium sulfate. Whileit is not essential for the preparation of lipoic acid, the product,ethyl 6-hydroxy-8-thiocyanooctanoate, can be isolated by removing thebenzene in vacuo and distilling the product at 200-205 C. at 1 mm.mercury pressure. Its index of refraction at 25 C. is 1.4860:0.0010.

.' A dry. reaction vessel which has provision for the exclusion ofatmospheric moisture is charged with 1627 parts of a benzene solutioncontaining about 660 parts of ethyl 6-hydroxy-8 thiocyanooctanoate and280 parts of dry pyridine. i The mixture is stirred and cooled to atemperature of 7 C. 342 parts of methane sulfonyl chloride is added tothe cooled mixture over a ten minute period. The mixture is stirred inthe cold for a period of three hours. It is allowed to stand for 14hours. 383 parts of anhydrous sodium bicarbonate is added to the mixturecooled to 4 C. The bicarbonate addition required a 15 minute period.After the mixture is stirred for a period of one hour the suspendedsalts are removed by filtration. The solution, which contains methylsulfonyl ester of ethyl 6-hydroxy-8-thiocyanooctanoate, is used in thenext step.

To the solution described in the preceding paragraph there is added 300parts-of potassium thiocyanate and 600 parts of dry dimethylformamide.The resulting mixture is stirred, heated and maintained at reflux for atwo hour period. During the heating a gel forms. The reaction mixture iscooled to room temperature, washed with four portions of water and driedover magnesium sulfate. Evaporation of the solvent in vacuo gives a darkoil which has an index of refraction of about 1.5060. This oilconsisting mainly of ethyl 6,8-dithiocyanoctanoate can be purified bydissolving it in an equal weight of benzene and passing the benzenesolution over a column of decolorizing charcoal. The resulting materialhas an index of refraction of 1.5081.

Two hundred and thirty parts of the crude ethyl 6,8-dithiocyanooetanoate is dissolved in 500 parts of alcohol. Thisalcoholic solution is added to a mixture comprising 358 parts ofpotassium hydroxide, 1000 parts of water and 2500 parts of alcohol. Theresulting mixture is heated for a period of six hours at refluxtemperature. It is then cooled to a temperature of 15 C. and made acidby the addition of concentrated hydrochloric acid. The precipitatedsalts are removed by filtration; the solvent is removed in vacuo usingthe heat of a steam bath.

The resulting mixture of oil, salts, and water is extracted withbenzene. The benzene extract is washed with water once and then driedover anhydrous magnesium sulfate. The benzene is evaporated in vacuo togive the desired product, alpha-lipoic acid, in crude form. The crudeproduct is distilled at l-200 C. at 0.5 to 1.0 mm. of mercury, andcrystallizes in the distillation receiver. Alpha-lipoic acid may berecrystallized from 15 to 20 times its weight of methyl cyclohexane togive compound melting at 5860 C.

Example 3 To a cooled mixture comprising 80 parts of methyl8-chloro-6-hydroxyoctanoate, prepared as in Example 1, and parts of drypyridine, there is added 50 parts of methane sulfonyl chloride at atemperature of 10 C. over a five minute period. After the mixture isstirred for one-half hour in the cold and an additional half-hour atroom temperature, 100 parts of anhydrous ether is added to precipitatethe by-product pyridine salt. This salt is removed by filtration.

After removal of the pyridine in vacuo the oily product is combined with80 parts of potassium thiocyanate and heated to 200 C. for a period of15 minutes. The reaction mixture is cooled and then treated with 100parts of alcohol to break up the mass and subsequently with water todissolve the salt and form an oily layer.

The oily layer is collected with 500 parts of tetrachloroethane. Thetetrochloroethane solution is then washed with successive portions ofwater, dilute sodium bicarbonate solution, dilute hydrochloric acid andwater. During the wash it is preferable to clarify the two phase systemby filtration thru Celite. The oil consisting mainly of crude methyl6,8-dithiocyanooctanoate and 7 11 V solvent is dried over magnesiumsulfate and .solvent is removed in vacuo. V I Fifty-six parts of crudemethyl 6,8-dithiocyanooctanoate is dissolved in 600 parts of alcohol andthe alcoholic solution is treated with 56 parts of potassium hydroxidedissolved in 100 parts of water at reflux temperature for a period ofone and one-half hours. A major portion of the solvent is removed invacuo to leave about 200 parts of crude reaction mixture. This mixtureis diluted with an equal volume of water and washed with ethyl acetate.The aqueous solution is then acidified with concentrated hydrochloricacid and extracted twice with ethyl acetate. The ethyl acetate solutionof aIpha-lipoic acid is washed with water and dried over sodium sulfate.After removal of the solvent in vacuo, the dl-alpha lipoic is purifiedby distillation.

I claim: 1. A compound of the formula where is an alkyl group of 1-6carbon atoms.

2. A compound of the formula 'aooownoroiL-onrcnz where R is an alkylgroup of 1-6 carbon atoms and Y and Z are different radicals but are ofthe class consisting of hydroxy and thiocyano radicals.

3. A compound of the formula ROOC(CH2)4CH-OHrCHz H SON where R is analkyl group of 1-6 carbon atoms.

4. Methyl 6,8-dithiocyanooctanoate. 5. Methyl6-hydroxy-8-thiocyanooctanoate.

No references cited.

1. A COMPOUND OF THE FORMULA
 2. A COMPOUND OF FORMULA